By William Elliott, MD, FACP, and James Chan, PharmD, PhD

Dr. Elliott is Assistant Clinical Professor of Medicine, University of California, San Francisco.
Dr. Chan is Associate Clinical Professor, School of Pharmacy, University of California, San Francisco.

The FDA has approved a new treatment for paroxysmal nocturnal hemoglobinuria (PNH), a rare, life-threatening blood disease. The previous therapeutic target for PNH treatment has been complement protein C5 (C5 inhibitors, eculizumab, and ravulizumab). Pegcetacoplan is a pegylated pentadecapeptide that targets complement C3, upstream in the complement cascade. It received fast-track, breakthrough therapy, and orphan designations, along with a priority review and accelerated approval.


Pegcetacoplan can be prescribed to adults with PNH.1


The recommended dose of pegcetacoplan is 1,080 mg by subcutaneous infusion twice weekly via a commercially available infusion pump that includes a reservoir of at least 20 mL.1 Pegcetacoplan is available as a single-dose vial containing 1,080 mg/20 mL. Similar to C5 inhibitors, pegcetacoplan is available only through a restricted program under a Risk Evaluation and Mitigation Strategy. Patients should be vaccinated against encapsulated bacteria (including Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae type B) at least two weeks before initiation of therapy according to current Advisory Committee on Immunization Practices guidelines.


Pegcetacoplan provides a different mechanism of action and superior control of hemolysis vs. eculizumab.1,2 Treatment was associated with a significant increase in hemoglobin levels.


Injection site reactions and diarrhea are more common with pegcetacoplan compared to eculizumab (39% vs. 5%; 22% vs. 3%, respectively).1,2 Vaccination against encapsulated bacteria lowers (but does not eliminate) risk of serious infections.1 Pegcetacoplan interferes with laboratory tests that use silica reagents in coagulation panels, resulting in artificially prolonged activated partial thromboplastin time.1


PNH is an acquired clonal disorder resulting in deficiency of complement regulatory proteins (CD55 and CD59), leading to complement-mediated intravascular hemolysis of susceptible red cells. Treatment with a C5 inhibitor, such as eculizumab, reduces hemolysis, cuts the need for transfusion, ameliorates anemia, lowers the risk of thrombosis, and improves quality of life. However, 25% of patients still need transfusions, some have breakthrough intravascular hemolysis and C3-related extravascular hemolysis caused by red cell opsonization by C3 fragments.3-5

The efficacy of pegcetacoplan was evaluated in subjects with PNH who had been treated with a stable dose of eculizumab for at least the previous three months and recorded hemoglobin levels lower than 10.5 g/dL.1,2 The study included three phases: a four-week run-in period (pegcetacoplan + eculizumab); a 16-week randomized, controlled phase (pegcetacoplan [n = 41] or eculizumab [n = 39]); and a 32-week open-label phase (pegcetacoplan only). The primary endpoint was the change in hemoglobin from baseline to week 16. Secondary endpoints were proportion of subjects who did not require a transfusion, change in absolute reticulocyte count (ARC), and score on the Functional Assessment of Chronic illness Therapy-Fatigue (FACIT-F) scale (range, 0-52). At baseline, mean hemoglobin level was 8.7 g/dL, 55% had undergone four or more transfusions in the previous 12 months, the mean reticulocyte count was 217 × 10-9/liter, and mean FACIT-F score was 32.

At week 16, mean change in hemoglobin from baseline was 2.37 g/dL for pegcetacoplan vs. -1.47 g/dL for eculizumab, an adjusted difference of 3.84 g/dL. Transfusion avoidance was 85% for pegcetacoplan vs. 15% for eculizumab. Mean change in ARC was -136 × 10-9 cells/L compared to 28 × 10-9 cells/L. The FACIT-F score showed a difference of 11.9 points in favor of pegcetacoplan, and 73% of subjects recorded at least a three-point score increase compared to 0% for eculizumab.


Pegcetacoplan is the first C3 inhibitor approved for PNH and provides therapeutic improvement over current C5 inhibitor therapy (e.g., eculizumab). It provides an alternative to patients inadequately controlled on eculizumab or ravulizumab, as well as an initial treatment option for treatment-naïve patients. These drugs are extremely expensive, with the annual cost of pegcetacoplan expected to be $458,000, which is similar to other drugs in this class. 


  1. Apellis Pharmaceuticals. Empaveli prescribing information. May 2021.
  2. Hillmen P, Szer J, Weitz I, et al. Pegcetacoplan versus eculizumab in paroxysmal nocturnal hemoglobinuria. N Engl J Med 2021;384:1028-1037.
  3. Fattizzo B, Kulasekararaj AG. Second-generation C5 inhibitors for paroxysmal nocturnal hemoglobinuria. BioDrugs 2020;34:149-158.
  4. Risitano AM, Marotta S. Toward complement inhibition 2.0: Next generation anticomplement agents for paroxysmal nocturnal hemoglobinuria. Am J Hematol 2018;93:564-577.
  5. Notaro R, Sica M. C3-mediated extravascular hemolysis in PNH on eculizumab: Mechanism and clinical implications. Semin Hematol 2018;55:130-135.